This invention is in the area of polymers for controlled delivery of substances, and more specifically encompasses biodegradable polyanhydrides whose end groups are terminated with fatty acids, and methods for making thereof.
There has been extensive research in the area of biodegradable controlled release systems for bioactive compounds. Biodegradable matrices for drug delivery are useful because they obviate the need to remove non-biodegradable drug-depleted devices. The ideal polymeric matrix would combine the characteristics of hydrophobicity, stability, organic solubility, low melting point, and suitable degradation profile. Such a polymer must be hydrophobic so that it retains its integrity for a suitable period of time when placed in an aqueous environment, such as the body, and stable enough to be stored for an extended period before use. The ideal polymer must also be strong, yet flexible enough so that it does not crumble or fragment during use.
Controlled release devices are typically prepared in one of several ways. For example, the polymer can be melted, mixed with the substance to be delivered, and then solidified by cooling. Such melt fabrication processes require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. Alternatively, the device can be prepared by solvent casting, where the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated, leaving the substance in the polymeric matrix. Solvent casting requires that the polymer be soluble in organic solvents.
Many polymers have been evaluated for their suitability for use as a matrix for a delivery device, including polyesters, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes. None of these polymers have exhibited all of the desired characteristics for use in the controlled delivery of substances.
Polyanhydrides have also been studied for use in controlled delivery devices, as reported by Leong, et al., J. Med. Biomed. Mater. Res. 19, 941 (1985); and J. Med. Biomed. Mater. Res. 20, 51 (1986). One of the first polyanhydrides studied for its controlled release behavior was poly(bis(p-carboxyphenoxy)methane anhydride), described by Rosen, et al., Biomaterials 4, 131 (1983). The aromatic polyanhydride exhibited near zero order (linear) erosion and release kinetics at 37.degree. C. and 60.degree. C. Shortly thereafter, three related polyanhydrides: poly 1,3-(bis(p-carbophenoxy)propane anhydride (p-CPP) (an aromatic polyanhydride); the polymer formed from the copolymerization of p-CPP with sebacic acid (a copolymer of an aromatic diacid and an aliphatic diacid); and polyterephthalic acid (an aromatic anhydride), were prepared and examined for release rates by Leong, et al., J. Med. Biomed. Mater. Res. 19, 941 (1985).
These aromatic polyanhydrides were found to have unacceptably slow degradation rates. For example, it was estimated that it would take a delivery device prepared from p-CPP more than three years to completely degrade in vivo. Further, anhydride homopolymers based on aromatic or linear aliphatic dicarboxylic acids were found to be highly crystalline and have poor film forming properties. Aromatic polyanhydrides also have high melting points and low solubility in organic solvents.
Polymers prepared from linear aliphatic diacids are hydrophilic solids that degrade by bulk erosion, resulting in a rapid release of the drug from the polymeric matrix. Consequently, linear aliphatic diacids are unsuitable for use in controlled drug delivery systems. Hydrophobicity of such polymers can be increased by copolymerizing the linear aliphatic diacids with aromatic diacids. This approach, however, results in an increase in the polymer melting temperature and a decrease in solubility in organic solvents. Furthermore, such copolymerization does not improve the drug release profile, but instead increases the degradation and the elimination time of the polymer both in vivo and in vitro. Since both homopolymers and copolymers of linear aliphatic diacids are very sensitive to moisture, they require storage under anhydrous and low temperature conditions.
As described in U.S. Pat. No. 4,757,128 to Domb and Langer, high molecular weight copolymers of aliphatic dicarboxylic acids with aromatic diacids are less crystalline than aromatic or linear aliphatic polyanhydrides, and they form flexible films. Degradation rates are also increased by copolymerizing an aromatic dicarboxylic acid with an aliphatic diacid. However, bulk erosion still occurs because areas of the polymer containing aliphatic anhydride linkages erode faster than aromatic anhydride linkages, forming channels in the matrix through which the substance to be delivered is released in an uncontrolled fashion. For example, in the p-CPP sebacic acid copolymer described above, the aliphatic anhydride bonds are cleaved in vivo and all of the drug is released in ten days, while the aromatic regions remain intact for another five and one-half months. Further, the copolymers have inferior mechanical properties; they become brittle and crumble into flakes on exposure to moisture.
U.S. Patents that describe the use of polyanhydrides for controlled delivery of substances include: U.S. Pat. No. 4,857,311 to Domb and Langer, entitled "Polyanhydrides with Improved Hydrolytic Degradation Properties," which describes polyanhydrides having a uniform distribution of aliphatic and aromatic residues in the chain, prepared by polymerizing a dicarboxylic acid with an aromatic end and an aliphatic end; U.S. Pat. No. 4,888,176 to Langer, et al., entitled "Controlled Drug Delivery High Molecular Weight Polyanhydrides," which describes the preparation of high molecular weight polyanhydrides in combination with bioactive compounds for use in controlled delivery devices; and U.S. Pat. No. 4,789,724 to Domb and Langer, entitled "Preparation of Anhydride Copolymers", which describes the preparation of very pure anhydride copolymers of aromatic and aliphatic diacids.
There remains a strong need, however, for a polymer having the desired characteristics of hydrophobicity, stability, strength, flexibility, organic solubility, low melting point, and appropriate degradation profile, for use as a matrix for controlled delivery devices. It would also be useful to be able to substantially alter the degradation and release kinetics of the polyanhydride for a wide variety of applications without significantly affecting the physical properties of the polymer.
It is therefore an object of the present invention to provide a biodegradable polymer that releases an incorporated substance in a controlled manner, wherein the polymer is highly hydrophobic, and degrades by surface erosion.
It is a further object of the present invention to provide a biodegradable, surface erodible polymer that is thermodynamically and hydrolytically stable, and can be stored under mild storage conditions.
It is a still further object of the present invention to provide a biodegradable controlled release microparticulate, injectable delivery system suitable for controlled in vivo administration of peptides and proteins, which is not acidic even in the absence of additives, and which stabilizes the incorporated peptides and proteins to be released without the use of additives.